Abstract Maintenance of the gut epithelial integrity under critical surgical conditions requires epithelial cells to rapidly elicit changes in gene expression patterns to regulate their survival, adapt to stress and keep epithelial homeostasis. Inhibition of mucosal growth occurs commonly in various critical surgical disorders, particularly in patients who undergo massive gastrointestinal surgical resections and are then supported with total parenteral nutrition (TPN). Because of our deficient understanding of the mechanism underlying this critical pathological process, effective therapies to maintain the mucosal epithelial integrity in patients with critical surgical illnesses are limited, leading to mucosal atrophy, maladaptation, delayed healing, impaired barrier function, and bacterial translocation. Recently, noncoding RNAs (ncRNAs) have emerged as a novel class of master regulators of gene expression and are fundamentally involved in many biological processes and various human diseases. In preliminary studies, our genome- wide miRNA and long ncRNA (lncRNA) expression profiles reveal that fasting-induced mucosal atrophy associates with an increase in miR-195 but with a decrease in lncRNA Uc-173. Tissue-specific miR-195 deletion in intestinal epithelial cells enhances gut mucosal hyperplasia, whereas Uc-173 silencing represses mucosal growth by increasing miR-195. Based on these exciting observations, we HYPOTHESIZE that a network of miR-195/lncRNA Uc-173 interactions plays an important role in maintaining the intestinal epithelial integrity under critical surgical conditions. Three specific aims are proposed to test the hypothesis: 1) to determine the exact role of miR-195 in gut mucosal growth and adaptation in critical surgical conditions and to further identify its targetome; 2) to determine whether lncRNA Uc-173 interacts functionally with miR-195 to jointly regulate intestinal mucosal growth and target mRNA expression in response to surgical stress; and 3) to define the mechanisms by which lncRNA Uc-173 regulates miR-195 transcription and biogenesis. Completion of these specific aims will make a significant conceptual advance by linking the miRNA/lncRNA interaction with gut mucosal regeneration and will create a fundamental base for developing novel therapies to maintain intestinal epithelial integrity in patients with critical surgical illness.